Landmark-based high-dimensional diffeomorphic maps of the hippocampus (although accurate) is highly-dependent on rater's anatomic knowledge of the hippocampus in the magnetic resonance images. It is therefore vulnerable to rater drift and errors if substantial amount of effort is not spent on quality assurance, training, and re-training. A fully-automated, FreeSurfer-initialized large-deformation diffeomorphic metric mapping procedure of small brain substructures, including the hippocampus, has been previously developed and validated in small samples. In this report, we demonstrate that this fully-automated pipeline can be used in place of the landmark-based procedure in a largesample clinical study to produce similar statistical outcomes. Some direct comparisons of the two procedures are also presented. © 2009 Wiley-Liss, Inc.